This invention relates generally to anti-inflammatory, topically applied nonsteroidal compositions and to their uses and relates more specifically to such compositions having as active ingredient .beta..sub.2 -adrenergic agonist(s).
Applicants emphasize that although there are at least hundreds (perhaps thousands) of .beta..sub.2 -agonists known in the art, only salbutamol has been disclosed as having any topical anti-inflammatory activity. It is believed that no structure-to-activity relationship for predicting topical anti-inflammatory activity is known in the art at this time. The art area is very unpredictable.
Inflammation is exhibited by most skin diseases. A variety of inflammatory skin diseases and conditions (including chronic and actue types) has resulted in an ongoing search for anti-inflammatory drugs.
The introduction of steroids provided the dermatologist with a class of anti-inflammatory agents that are therapeutically active against a wide spectrum of inflammatory skin diseases. However, the effect of steroids in many inflammatory conditions, particularly in those of a chronic nature, is only palliative and requires extended use. And such extended use of steroids also results in various adverse effects, including atrophy of skin, striae, telangiectasia, steroid acne, and adrenal supression, especially in children. Additionally, in various chronic inflammatory skin diseases, the termination of steroid therapy has led to the reappearance of inflammatory symptoms and sometimes with increased intensity. In response to the drawbacks of using steroids, over the last 20 years many new nonsteroidal anti-inflammatory agents (i.e., NSAIA) have been developed for use in various diseases, including rheumatic diseases. These compounds generally appear to be free of some of the adverse effects of steroids, especially tissue atrophy, adrenal suppression, and other less severe rebound effects.
One class of compounds included within the group of NSAIA is a group of compounds that are prostaglandin synthetase inhibitors. These materials are generally active in reducing UVB-induced erythema (i.e., erythema induced by ultraviolet light) in guinea pigs; but the materials are only slightly active or are inactive in other tests relating to dermatitis, including the croton oil and the oxazolone ear edema assays further described in the examples below. Therefore, other classes of nonsteroidal compounds with topical anti-inflammatory activity are of interest.
.beta. adrenergic agonists (including .beta..sub.1 and .beta..sub.2 agonists) are compounds which have been proposed to act through the stimulation of adenylate cyclase, resulting in the conversion of adenosine triphosphate (i.e., ATP) to cyclic 3',5',-adenosine monophosphate (i.e., C-AMP). See, for example, R. J. Brittain, et al, Adv. Drug Res. 5, 197, 1970. The walls of essentially all nucleated mammalian cells contain the enzyme adenylate cyclase, which is stimulated by various compounds including prostaglandin E and .beta.-adrenergic drugs.
Adenylate cyclase activity has been reported to be present in human and animal epidermis. Disorders in adenylate cyclase activity and in C-AMP levels have been reported in proliferative skin diseases such as eczema, psoriasis, epidermolytic hyperkeratosis and lamellar ichthyosis.
In short, .beta. agonists are a class of compounds which stimulate the adrenergic system of the human body.
Materials which are classified as .beta..sub.1 agonists are .beta. agonists which selectively react with the .beta..sub.1 receptors and elicit cardiac stimulation.
Materials which are classified as .beta..sub.2 agonists selectively react with the .beta..sub.2 receptors which are present in the smooth muscles of the blood vessels and bronchi; these materials elicit bronchodilation and vasodilation.
In British Pat. No. 4,323,575 to G. Jones, Apr. 6, 1982, disubstituted catecholamines (which may or may not be .beta..sub.2 agonists) having topical anti-inflammatory activity are disclosed.
In U.S. Pat. No. 3,341,584 to Larsen et al sulfonanilides having the general formula I are disclosed. ##STR1## As disclosed in that patent, the sulfonanilides of formula I, wherein Z is CHOH, are pharmacologically active phenethanolamines having actions which either resemble the effects of the adrenal medullary hormones or adrenergic neurotransmitters or oppose the effects of the adrenal medullary hormones or adrenergic neurotransmitters. Alkyl and aryl-sulfonamido nuclearly substituted phenalkanolamines have useful pharmacologic effects, suiting them variously as vasopressors, vasodepressors, analgesics, bronchodilators, .alpha.-receptor stimulants, .beta.-receptor stimulants, .alpha.-receptor blocking agents, .beta.-receptor blocking agents, papaverine-like smooth muscle depressants, or anti-inflammatory agents useful in controlling or preventing anaphylaxis.
Anaphylaxis is defined in the McGraw-Hill Dictionary of Scientific and Technical Terms, Second Edition, 1978, as hypersensitivity following parenteral injection of an antigen, wherein local or systemic allergenic reaction occurs when the antigen is reintroduced after a time lapse. Topical is defined to be "local or designed for local application" and that term is so used in this application. Therefore, because anaphylaxis and topical inflammations are different conditions physiologically, a drug which is useful in treating one of these conditions is generally not useful in treating the other condition.
In U.S. Pat. No. 3,801,631, 2-hydroxy-5'-[1-hydroxy-2-(2-methyl-1-phenyl-2-propylamino)ethyl] methanesulfonanilide, called zinterol (which is included within the broad genus of sulfonic acid amides disclosed in U.S. Pat. No. 3,341,584 cited above) is disclosed. Zinterol was there described as a potent anorexigenic agent, as a bronchodilator, and as having analgesic activity.
In the article "Adrenergic Sulfonanilides. 4. Centrally Active .beta.-Adrenergic Agonists", D. L. Temple et al, Journal of Medicinal Chemistry, Vol. 19, No. 5, Pgs. 626-633 (1976), zinterol (compound No. 43) is described as a potent anorexiant and as a narcotic antagonist.
Additionally, in U.S. Pat. No. 3,919,424 and in U.S. Pat. No. 3,993,776, further description of the uses of zinterol is given.
Salbutamol is a .beta..sub.2 agonist. This material was described in R. Seely et al, Proc. Soc. Exp. Biol. Med. 159, 223 (1978) as being useful as a topical anti-inflammatory agent.
The synthesis of salbutamol is described in Drugs of the Future IV, 629 (1979). There, salbutamol is indicated as being useful as an anti-inflammatory agent when applied locally. It is further stated that salbutamol given orally in the control of asthma compares favorably with related drugs. A mechanism for the action of salbutamol is proposed. (See page 631 of the reference.)
A 1980 publication by Saiichirou Seo et al, "Inhibition of Adjuvant Arthritis by Salbutamol and Aminophylline," European J. of Pharmacology, 63, 267-274, 1980, describes inhibition of swelling in the paws of mice by injections of combinations of salbutamol and aminophylline.
Other materials showing some structural similarity to zinterol and having topical anti-inflammatory activity are disclosed in U.S. Pat. No. 4,323,575 to Jones. These materials may or may not be .beta.-agonists and only testing would determine whether they are.
In U.S. Pat. No. 4,088,756 to Voorhees, other .beta.-agonists which may or may not have anti-inflammatory activity are disclosed.
However, as further described below, which .beta..sub.2 -agonists will be effective topical anti-inflammatory agents cannot be predicted with any reasonable degree of certainty. After much experimentation, applicants found that nearly all .beta..sub.2 agonists they tested for such activity were either ineffective, highly toxic, or both.
Therefore, despite what has been known in the prior art, there is a continuing need for non-steroidal anti-inflammatory drugs which exhibit consistently good anti-inflammatory activity and which are nontoxic.